Familial Limb Girdle Myasthenic Syndrome With Tubular Aggregates via the DPAGT1 Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from defects in presynaptic, synaptic, or post synaptic proteins. Clinically, a limb-girdle pattern of muscle involvement makes DOK7, AGRN, GFPT1, and DPAGT1-related CMS unique from other CMS. Belaya et al. (Am J Hum Genet 91:193-201, 2012) found mutations in the DPAGT1 gene (OMIM 191350) in four families with autosomal recessive limb-girdle myasthenic syndrome with tubular aggregates. Age of onset ranged from 6 month to 7 years of life. Presenting symptoms included proximal weakness; hypotonia and poor head control; difficulty walking; abnormal gait; and delayed motor development. Ptosis and ophthalmoplegia were documented in one of the five and none of five patients, respectively, among the four families. Scoliosis was present in 2/5 patients. Repetitive nerve stimulation revealed a decremental response in all five patients, and single-fiber EMG showed abnormal jitter and blocking. Tubular aggregates were seen in 4/4 muscle biopsies. Clinical symptoms were either stable or slowly progressive in all patients. All five affected subjects responded to acetylcholinesterase inhibitors and two patients showed improvement by taking 3,4-diaminopyridine, a drug which increases acetylcholine release from the nerve terminal. Patients with other forms of limb-girdle myasthenic syndrome with tubular aggregates also respond well to treatment with acetylcholinesterase inhibitors (Rodolico et al. Neuromusc Disord 12:964-969, 2002; Beeson et al. Science 313: 1975-1978, 2006).

Abnormalities of proteins involved with neuromuscular transmission underlie familial limb-girdle myasthenic syndrome, congenital myasthenic syndromes, Pena-Shokeir syndrome, and multiple pterygium syndromes. These disorders, which may represent a phenotypic continuum of a single entity, are most often inherited in an autosomal recessive manner. DPAGT1 encodes an enzyme that catalyzes the first committed step of N-linked protein glycosylation. Beyala et al. (2012) showed that DPAGT1 enzyme activity is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. Familial limb-girdle myasthenic syndrome with tubular aggregates due to DPAGT1 mutations is inherited as an autosomal recessive disorder (Belaya et al. 2012). Among the initial cohort of DPAGT1-related familial limb-girdle myasthenic syndrome patients, five missense and one single base deletion causative mutation were described (Bayala et al. 2012).

Acyl-CoA:diacylglycerol acyltransferase is encoded by exons 1–9 of the DPAGT1 gene.

DOK7, AGRN, GFPT1, and DPAGT1 mutations are the only known cause of familial limb-girdle myasthenic syndrome. Clinical sensitivity should be high for patients meeting rigorous clinical, histopathological, and electrophysiological criteria.

This test provides full coverage of all coding exons of the DPAGT1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).